title: Tamoxifen inhibits macrophage FABP4 expression through the combined effects of the GR and PPARγ pathways.
abstract: Macrophage adipocyte fatty acid-binding protein (FABP4) plays an important role in foam cell formation and development of atherosclerosis. Tamoxifen inhibits this disease process. In the present study, we determined whether the anti-atherogenic property of tamoxifen was related to its inhibition of macrophage FABP4 expression. We initially observed that tamoxifen inhibited macrophage/foam cell formation, but the inhibition was attenuated when FABP4 expression was selectively inhibited by siRNA.We then observed that tamoxifen and 4-hydroxytamoxifen inhibited FABP4 protein expression in primary macrophages isolated from both the male and female wild-type mice, suggesting that the inhibition is sex-independent. Tamoxifen and 4-hydroxytamoxifen inhibited macrophage FABP4 protein expression induced either by activation of GR (glucocorticoid receptor) or PPARγ (peroxisome-proliferator-activated receptor γ). Associated with the decreased protein expression, Fabp4 mRNA expression and promoter activity were also inhibited by tamoxifen and 4-hydroxytamoxifen, indicating transcriptional regulation. Analysis of promoter activity and EMSA/ChIP assays indicated that tamoxifen and 4-hydroxytamoxifen activated the nGRE (negative glucocorticoid regulatory element), but inhibited the PPRE (PPARγ regulatory element) in the Fabp4 gene. In vivo, administration of tamoxifen to ApoE (apolipoprotein E)-deficient (apoE-/-) mice on a high-fat diet decreased FABP4 expression in macrophages and adipose tissues as well as circulating FABP4 levels. Tamoxifen also inhibited FABP4 protein expression by human blood monocyte-derived macrophages. Taken together, the results of the present study show that tamoxifen inhibited FABP4 expression through the combined effects of GR and PPARγ signalling pathways. Our findings suggest that the inhibition of macrophage FABP4 expression can be attributed to the antiatherogenic properties of tamoxifen.
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 30071, China.
authors.forename: Meixiu
authors.initials: M
authors.lastname: Jiang
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Xingzhe
authors.initials: X
authors.lastname: Ma
authors.forename: Wenquan
authors.initials: W
authors.lastname: Hu
authors.forename: Yuanli
authors.initials: Y
authors.lastname: Chen
authors.forename: Miao
authors.initials: M
authors.lastname: Yu
authors.forename: Qixue
authors.initials: Q
authors.lastname: Wang
authors.forename: Xiaoju
authors.initials: X
authors.lastname: Li
authors.forename: Zhinan
authors.initials: Z
authors.lastname: Yin
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Xiumei
authors.initials: X
authors.lastname: Gao
authors.forename: David P
authors.initials: DP
authors.lastname: Hajjar
authors.forename: Yajun
authors.initials: Y
authors.lastname: Duan
authors.forename: Jihong
authors.initials: J
authors.lastname: Han
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012737:Sex Factors; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology*; D014158:Transcription, Genetic
chemical_list: C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; D047495:PPAR gamma; D011965:Receptors, Glucocorticoid; D013629:Tamoxifen